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Träfflista för sökning "WFRF:(Dorst Johannes) "

Sökning: WFRF:(Dorst Johannes)

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2.
  • Freischmidt, Axel, et al. (författare)
  • Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
  • 2015
  • Ingår i: Nature Neuroscience. - 1097-6256 .- 1546-1726. ; 18:5, s. 631-
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
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3.
  • Hjorth, J. J. Johannes, et al. (författare)
  • The microcircuits of striatum in silico
  • 2020
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:17, s. 9554-9565
  • Tidskriftsartikel (refereegranskat)abstract
    • The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, somadendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.
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4.
  • Andersen, Peter M., 1962-, et al. (författare)
  • Therapeutic decisions in ALS patients : cross-cultural differences and clinical implications
  • 2018
  • Ingår i: Journal of Neurology. - : Springer Berlin/Heidelberg. - 0340-5354 .- 1432-1459. ; 265:7, s. 1600-1606
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Quantitative analysis of decision-making on therapeutic options in different sociocultural context in amyotrophic lateral sclerosis (ALS).Methods: ALS patients (n = 244) were consecutively recruited in Germany (n = 83), Poland (n = 83), and Sweden (n = 78) in a prospective cross-cultural study (www.NEEDSinALS.com). They were interviewed on preferences for therapeutic techniques including invasive (IV) and non-invasive ventilation (NIV), as well as percutaneous endoscopic gastrostomy (PEG) and on hypothetical termination of these using quantitative questions. Using standardized questionnaires, religiousness, personal values, quality of life, and depressiveness were assessed.Results: NIV was most frequently used in Germany and PEG in Sweden. Swedish patients were most liberal on initiation and termination of PEG, NIV and IV. Polish patients were mostly undecided and were least likely to consider discontinuing supportive management. Current use was partly associated with age, gender and state of physical function; also, financial support explained some variance. Future preferences on therapeutic options from the patient’s perspective were also closely associated with cultural factors. The more oriented towards traditional and conservative values, the less likely patients were to decide for invasive therapeutic devices (IV, PEG), the least likely to have ideations to discontinue any device and the more likely to have an undecided attitude.Conclusions: Current use of therapeutic options is determined by medical condition in analogy to clinical guidelines. For future considerations, other factors such as cultural background are crucial, yielding hurdles to be regarded in the implementation of advanced directives in a multicultural environment.
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5.
  • Brenner, David, et al. (författare)
  • Hot-spot KIF5A mutations cause familial ALS
  • 2018
  • Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 688-697
  • Tidskriftsartikel (refereegranskat)abstract
    • Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
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6.
  • Mueller, Kathrin, et al. (författare)
  • Comprehensive analysis of the mutation spectrum in 301 German ALS families
  • 2018
  • Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 89:8, s. 817-827
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.Methods Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.Conclusions We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.
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